An efficient method has been developed for the first solid-phase synthesis of HTLV-1 protease inhibitors that contain hydroxyethylamine isostere as a transition-state mimetic. The synthetic procedure was designed to allow the evaluation of stereostructure- activity relationships at the scissile site. All the possible configurations at the hydroxy- and side chain-bearing asymmetric centers of the isostere were constructed by an ester-derived asymmetric aldol reaction. Each inhibitor containing the isostere backbone was synthesized on solid support by using the newly developed succinate ester linker. The configuration at the hydroxy- and side chain-bearing asymmetric center showed remarkable effects on the inhibitory activity; the Ki value changed with approximately 2 orders of magnitude. The described approach enables an efficient preparation of the inhibitors containing secondary alcohol as a transition-state mimetic.
|Number of pages||9|
|Journal||Journal of Organic Chemistry|
|Publication status||Published - 2003 Jun 13|
ASJC Scopus subject areas
- Organic Chemistry